Ibuprofen Inhibits Colitis-Induced Overexpression of Tumor-Related Rac1b

The serrated pathway to colorectal tumor formation involves oncogenic mutations in the BRAF gene, which are sufficient for initiation of hyperplastic growth but not for tumor progression. A previous analysis of colorectal tumors revealed that overexpression of splice variant Rac1b occurs in around 80% of tumors with mutant BRAF and both events proved to cooperate in tumor cell survival. Here, we provide evidence for increased expression of Rac1b in patients with inflamed human colonic mucosa as well as following experimentally induced colitis in mice. The increase of Rac1b in the mouse model was specifically prevented by the nonsteroidal anti-inflammatory drug ibuprofen, which also inhibited Rac1b expression in cultured HT29 colorectal tumor cells through a cyclooxygenase inhibition.independent mechanism. Accordingly, the presence of ibuprofen led to a reduction of HT29 cell survival in vitro and inhibited Rac1b-dependent tumor growth of HT29 xenografts. Together, our results suggest that stromal cues, namely, inflammation, can trigger changes in Rac1b expression in the colon and identify ibuprofen as a highly specific and efficient inhibitor of Rac1b overexpression in colorectal tumors. Our data suggest that the use of ibuprofen may be beneficial in the treatment of patients with serrated colorectal tumors or with inflammatory colon syndromes.     

Instability at the FRA8I common fragile site disrupts the genomic integrity of the KIAA0146, CEBPD and PRKDC genes in colorectal cancer

Specific patterns of genomic aberrations have been associated with different types of malignancies. In colorectal cancer, losses of chromosome arm 8p and gains of chromosome arm 8q are among the most common chromosomal rearrangements, suggesting that the centromeric portion of chromosome 8 is particularly sensitive to breakage. Genomic alterations frequently occur in the early stages of tumorigenesis at specific genomic regions known as common fragile sites (cFSs). CFSs represent parts of the normal chromosome structure that are prone to breakage under replication stress. In this study, we identified the genomic location of FRA8I, spanning 530 kb at 8q11.21 and assessed the composition of the fragile DNA sequence. FRA8I encompasses KIAA0146, a large protein-coding gene with yet unknown function, as well as CEBPD and part of PRKDC, two genes encoding proteins involved in tumorigenesis in a variety of cancers. We show that FRA8I is unstable in lymphocytes and epithelial cells, displaying similar expression rates. We examined copy number alteration patterns within FRA8I in a panel of 25 colorectal cancer cell lines and surveyed publically available profiles of 56 additional colorectal cancer cell lines. Combining these data shows that focal recombination events disrupt the genomic integrity of KIAA0146 and neighboring cFS genes in 12.3% of colorectal cancer cell lines. Moreover, data analysis revealed evidence that KIAA0146 is a translocation partner of the immunoglobulin heavy chain gene in recurrent t(8;14)(q11;q32) translocations in a subset of patients with B-cell precursor acute lymphoblastic leukemia. Our data molecularly describe a region of enhanced chromosomal instability in the human genome and point to a role of the KIAA0146 gene in tumorigenesis.     

Clinical outcomes following 3D image-guided brachytherapy for vaginal recurrence of endometrial cancer

Purpose

To evaluate clinical outcomes for women with recurrent endometrial cancer treated with 3D image-guided brachytherapy

Methods and materials

44 women, of whom 13 had received prior RT, received salvage RT for vaginal recurrence from 9/03 to 8/11. HDR or LDR interstitial brachytherapy was performed under MR or CT guidance in 35 patients (80%); 9 (20%) had CT-guided HDR cylinder brachytherapy. The median cumulative dose in EQD2 was 75.5 Gy. Actuarial estimates of local failure (LF), disease-free (DFS) and overall survival (OS) were calculated by Kaplan–Meier.

Results

Histologic subtypes were endometrioid (EAC, 33), papillary serous/clear cell (UPSC/CC, 5) and carcinosarcoma (CS, 6). The 2-year DFS/OS rates were 75%/89% for EAC and 11%/24% for UPSC/CC/CS (both p < 0.01). On MVA, high tumor grade was associated with recurrence (HR 3.2 for grade 2, 9.6 for grade 3, p < 0.01). The LF rate at 2 years was 4% for patients without versus 39% for those with prior RT (p = 0.1). Patients who had prior RT received lower cumulative doses at recurrence (66.5 Gy vs. 74.4 Gy, p < 0.01). The 2-year DFS/OS rates with and without prior RT were 26%/55% and 72%/80% (both p = 0.1). Four patients (9%) experienced grade 3 late toxicity, including 3 of 13 (23%) in the re-irradiation setting and 1 of 31 (3%) with no prior radiotherapy.

Discussion

3D image-guided brachytherapy results in excellent local control for women with recurrent endometrial cancer, particularly with cumulative EQD2 doses greater than 70 Gy. Successful salvage of vaginal recurrence is related to tumor grade and histologic subtype.     

Psychological Correlates of Sexual Dysfunction in Female Rectal and Anal Cancer Survivors: Analysis of Baseline Intervention Data

IntroductionSexual dysfunction represents a complex and multifactorial construct that can affect both men and women and has been noted to often deteriorate significantly after treatment for rectal and anal cancer. Despite this, it remains an understudied, underreported, and undertreated issue in the field of cancer survivorship.AimThis study examined the characteristics of women enrolled in an intervention trial to treat sexual dysfunction, and explored the relationship between sexual functioning and psychological well‐being.MethodsThere were 70 female posttreatment anal or rectal cancer survivors assessed as part of the current study. Participants were enrolled in a randomized intervention trial to treat sexual dysfunction and completed outcome measures prior to randomization.Main Outcomes MeasuresThe main outcome measures are quality of life (QOL) (European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire [EORTC‐QLQ‐C30] and Colorectal Cancer‐Specific Module [QLQ‐CR38]), sexual functioning (Female Sexual Functioning Index), and psychological well‐being (Brief Symptom Inventory Depression/Anxiety, Impact of Events Scale‐Revised, CR‐38 Body Image).ResultsWomen enrolled in the study intervention were on average 55 years old, predominantly Caucasian (79%), married (57%), and a median of 4 years postprimary treatment. For those reporting sexual activity at baseline (N = 41), sexual dysfunction was associated with a range of specific measures of psychological well‐being, all in the hypothesized direction. The Sexual/Relationship Satisfaction subscale was associated with all measures of psychological well‐being (r = ?0.45 to ?0.70, all P < 0.01). Body image, anxiety, and cancer‐specific posttraumatic distress were notable in their association with subscales of sexual functioning, while a global QOL measure was largely unrelated.ConclusionsFor sexually active female rectal and anal cancer survivors enrolled in a sexual health intervention, sexual dysfunction was significantly and consistently associated with specific measures of psychological well‐being, most notably Sexual/Relationship Satisfaction. These results suggest that sexual functioning may require focused assessment by providers, beyond broad QOL assessments, and that attention to Sexual/Relationship Satisfaction may be critical in the development and implementation of interventions for this cohort of patients. Philip EJ, Nelson C, Temple L, Carter J, Schover L, Jennings S, Jandorf L, Starr T, Baser R, and DuHamel K. Psychological correlates of sexual dysfunction in female rectal and anal cancer survivors: Analysis of baseline intervention data. J Sex Med 2013;10:2539–2548.     

Association between a cannabinoid receptor gene (CNR1) polymorphism and cannabinoid-induced alterations of the auditory event-related P300 potential

The biochemical sequelae that follow traumatic brain injury (TBI) are numerous and affect many different brain functions at different points of time as the secondary cascades progress. The complexity of the resulting pathophysiology is such that a singular therapeutic intervention may not provide adequate benefit and a combination of drugs targeting different pathways may be needed. Two of the most widely studied injury mechanisms are oxidative stress and inflammation. Numerous studies have suggested that pharmacological agents targeting either of these pathways may produce an improvement in histological and functional outcome measures. We hypothesized that combining melatonin, a potent antioxidant, with minocycline, a bacteriostatic agent that also inhibit microglia, would provide better neuroprotection than either agent used alone. To test this hypothesis, we subjected anesthetized adult male rats to a 1.5mm controlled cortical impact and administered melatonin or vehicle in the acute post-injury period followed by daily minocycline or vehicle injections beginning the following day in a 2×2 study design. The animals were allowed to recover for 5 days before undergoing Morris water maze (MWM) testing to assess cognitive functioning following injury. There was no significant difference in MWM performance between the vehicle, melatonin, minocycline, or combination treatments. Following sacrifice and histological examination for neuroprotection, we did not observe a significant difference between the groups in the amount of cortical tissue that was spared nor was there a significant difference in [(3)H]-PK11195 binding, a marker for activated microglia. These results suggest that neither drug has therapeutic efficacy, however dosing and/or administration issues may have played a role.     

Periodontal disease as a risk factor for cardiovascular disease: suggestion of a further link in systemic lupus erythematosus

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Due to either infection or disease activity, elevated levels of inflammatory markers and up-regulation of the autoimmune process can contribute to the development of atherosclerosis in SLE patients. Periodontal diseases are among the most prevalent chronic infections in humans and are characterized by pathogen-induced oral inflammatory disease affecting the supporting tissues of teeth. Several cytokines capable of inducing systemic effects are produced during the course of this infection. The presence of these cytokines can be verified by changes in the levels of C-reactive protein (CRP). Periodontal disease is a well-known risk factor for atherosclerosis. The potential for beneficial prevention of CVD events through the use of periodontal treatment has been previously recommended. This review reinforces the hypothesis that periodontal infection could be a risk factor for CVD in patients diagnosed with SLE, and suggests that by reducing the progression of this oral infection, levels of inflammatory markers common to both diseases (SLE and periodontal disease) would likely decrease.